HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)

HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional) is sponsored by National Institutes of Health (NIH) HEAL Initiative. This funding opportunity supports the development of non-addictive analgesic therapeutics (small molecules and biologics) to treat pain, which is relevant to addressing the opioid crisis.

Expired RFA-NS-21-010: HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional) This notice has expired. Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and National Eye Institute ( NEI ) National Institute on Alcohol Abuse and Alcoholism ( NIAAA ) National Institute of Arthritis and Musculoskeletal and Skin Diseases ( NIAMS ) Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) National Institute of Dental and Craniofacial Research ( NIDCR ) National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) National Institute on Drug Abuse ( NIDA ) National Center for Complementary and Integrative Health ( NCCIH ) National Heart, Lung, and Blood Institute ( NHLBI ) All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers.

The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Office of Research on Women's Health ( ORWH ) Funding Opportunity Title HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional) UG3 / UH3 Exploratory/Developmental Phased Award Cooperative Agreement Notices of Special Interest associated with this funding opportunity November 2, 2023 - This RFA has been reissued as RFA-NS-24-019 NOT-OD-22-190 - Adjustments to NIH and AHRQ Grant Application Due Dates Between September 22 and September 30, 2022 August 12, 2022 - Notice of Change to RFA-NS-21-010.

See Notice NOT-NS-23-016 . February 16, 2022 - Notice of Change to Key Dates for RFA-NS-21-010, "HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)".

See Notice NOT-NS-22-077 October 28, 2021 - Reminder: FORMS-G Grant Application Forms & Instructions Must be Used for Due Dates On or After January 25, 2022 - New Grant Application Instructions Now Available. See Notice NOT-OD-22-018 . September 13, 2021 - Updates to the Non-Discrimination Legal Requirements for NIH Recipients.

See Notice August 5, 2021 - New NIH "FORMS-G" Grant Application Forms and Instructions Coming for Due Dates on or after January 25, 2022. August 5, 2021 - Update: Notification of Upcoming Change in Federal-wide Unique Entity Identifier Requirements. See Notice NOT-OD-21-170 April 20, 2021 - Expanding Requirement for eRA Commons IDs to All Senior/Key Personnel.

See Notice NOT-OD-21-109 October 26, 2021 - Notice of NHLBI Participation in RFA-NS-21-010. See Notice NOT-HL-21-039 . September 7, 2021 - Notice of Change to Application Types Allowed for RFA-NS-21-010.

See Notice NOT-NS-22-025 . September 7, 2021 - Notice of Change to Key Dates for RFA-NS-21-010 "HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)". See Notice NOT-NS-22-021 .

November 25, 2020 - Notice of Removal of Cost Matching Requirements for RFA-NS-21-010. See Notice NOT-NS-21-016 . Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity See Section III.

3. Additional Information on Eligibility . Catalog of Federal Domestic Assistance (CFDA) Number(s) 93.

853; 93. 273, 93. 866, 93.

213; 93. 867; 93. 273; 93.

846; 93. 865; 93. 279; 93.

121; 93. 847; 93. 313; Funding Opportunity Purpose The purpose of this funding opportunity announcement (FOA) is to support preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat pain.

The goal of the program is to accelerate the optimization and development of promising small molecule and biologic hits/leads to Phase I clinical trials and readiness for the Early Phase Pain Investigation Clinical Network (EPPIC-Net) https://heal. nih. gov/research/clinical-research/eppic-net or other Phase II clinical studies .

Applicants must have a promising biologic or small molecule hit/lead, robust biological rationale for the intended approach, and identified assays for optimization of the agent.

The scope of this program includes optimization and early development activities, IND-enabling studies, development of a pharmacodynamic/target engagement biomarker, assembly and filing of an Investigational New Drug (IND) application and Phase I clinical testing.

This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress. Open Date (Earliest Submission Date) Letter of Intent Due Date(s) 30 days prior to receipt date.

November 18, 2020, March 24, 2021, July 14, 2021, October 15, 2021, February 15, 2022, June 15, 2022, October 14, 2022, February 14, 2023, June 15, 2023, October 17, 2023 by 5:00PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates. All applications are due by 5:00 PM local time of applicant organization.

All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s). Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date. AIDS Application Due Date(s) Standard dates apply, by 5:00 PM local time of applicant organization.

All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

February 2021, June 2021, October 2021, February 2022, June 2022, October 2022, February 2023, June 2023, October 2023, February 2024 May 2021, October 2021, January 2022, May 2022, October 2022, January 2023, May 2023, October 2023, January 2024, May 2024 June 2021, November 2021, February 2022, April 2022, November 2022, February 2023, June 2023, November 2023, February 2024, June 2024 New Date November 2, 2023 (Original Date: May 8, 2023) per issuance of RFA-NS-24-019 Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide ,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV . When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review. Part 1. Overview Information Part 2.

Full Text of Announcement Section I. Funding Opportunity Description Section II. Award Information Section III.

Eligibility Information Section IV. Application and Submission Information Section V. Application Review Information Section VI.

Award Administration Information Section VII. Agency Contacts Section VIII. Other Information Part 2.

Full Text of Announcement Section I. Funding Opportunity Description The purpose of this funding opportunity announcement (FOA) is to support preclinical optimization and development of safe, effective, and non-addictive analgesic small molecule and biologic therapeutics to treat pain.

The goal of the program is to accelerate the optimization and development of promising small molecule and biologic hits/leads towards Phase I clinical trials and readiness for the Early Phase Pain Investigation Clinical Network (EPPIC-Net) https://heal. nih. gov/research/clinical-research/eppic-net or other Phase II clinical studies.

Applicants must have a promising small molecule or biologic hit/lead, robust biological rationale for the intended approach, and identified assays for optimization of the agent. The scope of this program includes optimization and early development activities, IND-enabling studies, pharmacodynamic or target engagement biomarker development, assembly of an Investigational New Drug (IND) application, and phase I clinical studies.

This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress. This study is part of the NIH's Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis.

The NIH HEAL Initiative will bolster research across the NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://www. nih.

gov/research-training/medical-research-initiatives/heal-initiative . More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an over reliance on opioids for chronic pain despite their poor ability to improve function.

This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options for pain are thus critically needed. As part of the mission of the HEAL Initiative, NINDS is working with other NIH Institutes and Centers to encourage the translation of basic research into new non-addictive pain treatments.

This program announcement is intended to create a foundation to initiate the optimization and development of pain therapeutics and catalyze the development of partnerships between the academic and industrial sectors so that translational research in pain can flourish as a cooperative, iterative process leading to safe, effective, and non-addictive treatments for pain.

To facilitate the discovery and development of therapeutics for pain researchers have the opportunity to collaborate with NIH-funded consultants and contract research organizations (CROs) that specialize in medicinal chemistry and Good Manufacturing Practices (GMP) manufacturing, pharmacokinetics, PET ligand development, biomarker assay validation, pharmacodynamics and related biomarkers,toxicology, formulations development, and Phase I clinical studies.

The NIH offers researchers funding for drug discovery and development activities that can be conducted in their own laboratories. This Funding Opportunity Announcement (FOA) invites applications for new non-addictive pain therapeutic projects.

The Program Director/Principal Investigator (PD/PI) will be responsible for conducting or leading all studies that involve disease- or target-specific assays, models, and other research tools such as target engagement or pharmacodynamic biomarkers.

A PD/PI with, for example, medicinal chemistry expertise and resources, may request funding to conduct structure-activity relationship (SAR) studies in his or her own lab but collaborate with contractors on in vitro ADMET, in vivo PK, drug manufacturing and IND-enabling toxicology studies.

By contrast, a PD/PI with limited experience in drug discovery and development may opt to collaborate with NIH contractors for all activities not related to disease or target biology. Applicants may propose to conduct all drug discovery and development activities themselves or collaborate with NIH contractors on activities of their choice.

For each project funded under this FOA, the NIH will assemble a customized Lead Development Team (LDT). The LDT will be co-chaired by the PD/PI and a NIH consultant and will include members of the PD/PI's team, additional subject matter expert consultants, and NIH staff.

The LDT will establish an overall strategy for the project, including milestones proposals, plan studies to be conducted by NIH contractors, and coordinate activities across different research sites.

Potential applicants are strongly encouraged to contact NIH Scientific/Research staff and participating NIH Institutes/Centers prior to preparing an application to discuss how they may best utilize NIH contract resources and whether their application fits the mission of a particular NIH IC. See also Applicant Webinar information under Section IV. 7 below ("Other Submission Requirements and Information").

This program announcement is specifically focused on the preclinical translational development necessary to advance small molecule and biologic non-addictive therapeutics for pain to Phase I clinical testing. The program supports preclinical optimization and development of small molecules and biologics leading to the assembly and submission of an IND application and the implementation of phase I clinical studies.

The scope of this program excludes basic research, and studies of disease mechanism or mechanistic/mechanism of action studies of the intended therapeutic. Further, development of animal models, diagnostics, rehabilitation strategies, or therapeutic devices is out of scope. Projects must enter at the UG3 phase of the program.

Projects may enter the program at the Discovery or Development stage. For entry at the Discovery Stage, projects must have a promising small molecule or biologic starting point for optimization, a rigorous biological rationale for the intended approach, and scientifically sound assays to test the agent. Applications for entry into the Development stage must have identified the candidate therapeutic.

In addition, a strong package of data linking the putative therapeutic target to the proposed disease indication and supporting the hypothesis that altering the target activity will produce desirable outcomes for the disease is required. Finally, the proposed therapeutic must have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use.

For the UG3 phase, this FOA encourages projects proposing the following optimization activities: Optimization using potency and efficacy screens Preliminary efficacy and toxicology testing in appropriate animal models for pain Characterization and testing for ADME (absorption, distribution, metabolism, and excretion) Initial development of pharmacodynamic/target engagement biomarkers associated with the therapeutic target or pathway It is expected that by the end of the UG3 phase, awardees will have characterized and selected a lead candidate that is ready for in vivo efficacy testing, though additional optimization may be necessary.

For advancement to the UH3 phase, the following development activities are in scope: Any further optimization activities as listed above, if needed Non-GLP toxicology studies (e.g. dose range finding toxicology) Pharmacodynamic (PD) and related target engagement biomarker studies Formulation and stability studies Cell bank development and testing Biodistribution, tumorigenicity, and immunogenicity Manufacturing of candidate therapeutics for IND IND-enabling safety pharmacology, genotoxicity, hERG and toxicology studies Activities considered Nonresponsive of this Announcement The following activities are considered nonresponsive: Screening to identify hit compounds Basic research and studies of disease mechanism Development of diagnostics and diagnostic devices Studies directed beyond Phase I clinical testing Opioid sparing projects and projects targeting mu-opioid To support these projects, additional existing NIH resources may be made available to the applicant outside of this grant budget.

Applicants are strongly encouraged to contact NIH staff to discuss these options.

These resources include, but are not limited to the following: NINDS has established contract support for Medicinal chemistry (including synthesis/SAR, computational chemistry and in vitro ADMET), pharmacokinetic studies, toxicology (GLP and non-GLP) and safety testing, drug formulation and manufacture, and phase I clinical studies and can provide access to experts in therapeutics development through a consulting service. .

Applicants must contact NINDS staff (contacts provided below) in order to utilize these resources and determine how to best leverage these as part of the application. As appropriate, applicants are encouraged to make use of the NINDS Common Data Elements ( https://www. commondataelements.

ninds. nih. gov/#page=Default ).

Applicants are also strongly encouraged to utilize the state-of-the-art capabilities at the NIH National Center for Advancing Translational Sciences (NIH/NCATS). Depending on the nature of the proposed collaboration, NCATS will make available its comprehensive capabilities in support of HEAL initiatives.

The capabilities include, but are not limited to, screening and scalable production of relevant stem cells; biofabrication of 3D functional tissues for drug testing; using quantitative high-throughput screening to identify promising compounds to be optimized by medicinal chemists; and implementing IND-enabling studies. A more detailed description of the capabilities can be found at: https://ncats. nih.

gov/heal/intramural-capabilities* and https://ncats. nih. gov/alliances/forms .

Because therapeutics optimization and development are inherently high risk, it is expected that there will be significant attrition as projects progress. Go/No-Go milestones will be established by a team consisting of the PD/PI and NIH program staff at the start of each project and updated as needed.

These milestones will be based upon a template outline of achievements necessary to progress through the stages of therapeutic development, but will be tailored to the specific therapeutic and its intended disease indication. NIH program staff and leadership will conduct an annual administrative review. At the end of the UG3 phase, NIH program staff and leadership will determine if the project will advance to the UH3 phase.

If needed, additional meetings to administratively review progress may take place. If justified, future year milestones may be revised based on data and information obtained during the previous project period.

The reviews will be based on: Successful achievement of milestones The overall feasibility of project advancement, considering data that may not have been captured in milestones Competitive landscape for the disease indication and drug target HEAL Programmatic priorities Since the ultimate goal of this program is to bring new pain therapeutics to the market, the creation and protection of appropriate intellectual property are significant considerations in designing research strategies and prioritizing projects for funding.

Each applicant is expected to address intellectual property issues related to the proposed therapeutics, with input from the institution's technology transfer officials, if applicable. Peer reviewers will be instructed to comment on the intellectual property landscape for each application. The project milestone plan may include commercialization milestones to protect and leverage intellectual property.

Recipients of awards are encouraged to identify potential licensing and commercialization partners early in the therapy development process. The PD(s)/PI(s) is encouraged to work closely with technology transfer officials at his or her institution, if applicable, to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner. See Section IV.

2. Other Project Information for details. The program provides funding through the UG3/UH3 cooperative agreement mechanism.

As a cooperative agreement, implementation will involve participation of NIH program staff in the planning and execution of the therapy-directed projects. This program is envisioned as a two stage UG3 and UH3 program. The UG3 portion of the award is designed to support optimization research for the first two years.

Our goal is to fund ~5 projects in each of FY21, FY22, FY23 appropriations permitting with projects having a limited budget for the first two years during the UG3 phase.

Based on the progress to milestones, only a limited number of projects will proceed to the UH3 phase for the remainder of the award period which will include final optimization and development leading to IND-enabling studies, either through the grant budget or through contract resources outlined above.

IC-Specific Areas of Interest The National Center for Complementary and Integrative Health (NCCIH) will support research on optimization and development of safe and non-addictive therapies for acute or chronic pain conditions, including chronic low back pain, that are treated with complementary and integrative health approaches.

Examples of complementary and integrative health approaches relevant to this FOA include, but are not restricted to, herbal products, dietary supplements, special diets, microbial metabolites, probiotics, microbial based therapies, or a combination of any of these therapies with each other or with conventional pharmacological therapies.

NIAAA is interested in developing novel non-addictive small molecules/biologicals to treat alcoholic neuropathic pain as well as treatment options for coexisting chronic pain and excessive alcohol use/AUD subjects.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is interested in supporting research aimed at developing novel, non-addictive pharmacotherapies for (1) more effective and safer treatment of pain in pediatric or obstetric populations; (2) the treatment of chronic gynecologic pain syndromes, including vulvodynia/vestibulodynia, chronic pelvic pain, and dysmenorrhea, and post-operative gynecologic pain; (3) the management of persistent pain associated with multiple chronic conditions in individuals with physical impairments.

Investigators are strongly encouraged to discuss their research plans with NICHD Scientific/Research contact prior to submitting their application. The NIDDK encourages applications for research to develop therapies and technologies for pain conditions within the mission of NIDDK.

Topics of special interest include, but are not limited to the pain associated with diabetic neuropathy; urologic chronic pelvic pain syndromes such as Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome; urinary stone disease and post-ureteroscopy stent-associated pain; functional gastrointestinal and motility disorders such as gastroparesis and irritable bowel syndrome; inflammatory bowel disease; hepatobiliary diseases such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and biliary dyskinesia; and exocrine pancreatic diseases such chronic pancreatitis.

See Section VIII. Other Information for award authorities and regulations. Section II.

Award Information Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.

2 for additional information about the substantial involvement for this FOA. Application Types Allowed The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Optional: Accepting applications that either propose or do not propose clinical trial(s) Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards NIH intends to fund an estimated 5 awards for fiscal year 2021. Future awards will depend on annual appropriations.

Application budgets must reflect the actual needs of the proposed project but should not include the costs of NIH contract resources requested. The total duration may not exceed 5 years. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education: Hispanic-serving Institutions Historically Black Colleges and Universities (HBCUs) Tribally Controlled Colleges and Universities (TCCUs) Alaska Native and Native Hawaiian Serving Institutions Asian American Native American Pacific Islander Serving Institutions (AANAPISIs) Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized) Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Institutions) Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.

System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.

gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants.

gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants. gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account.

PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support.

Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement. 3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.

A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application. An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101 ). Section IV.

Application and Submission Information 1. Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution.

Links to apply using ASSIST or Grants. gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. By the date listed in Part 1.

Overview Information , prospective applicants are asked to submit a letter of intent that includes the following information: Descriptive title of proposed activity Name(s), address(es), and telephone number(s) of the PD(s)/PI(s) Names of other key personnel Participating institution(s) Number and title of this funding opportunity For applicants with interest in small molecules, the letter of intent should be sent to: National Institute of Neurological Disorders and Stroke (NINDS) All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA. All instructions in the SF424 (R&R) Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information All instructions in the SF424 (R&R) Application Guide must be followed. The following additional instructions apply: Applications must include an Intellectual property (IP) strategy ( 2 pages maximum). Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials.

For Discovery stage projects, applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or commercial development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed.

If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status. For Development stage projects, applicants should describe their efforts to confirm that there are unlikely to be IP or other legal constraints that could block or impede development or commercialization of the proposed compounds.

If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status. SF424(R&R) Senior/Key Person Profile All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

Budget Justification: All for-profit applicants must document the matching (non-Federal) component and the federal (non-matching) component in the total project budget. That is, the requested budget plus the cost-matching budget must be detailed in tabular format to document the cost-matching (non-Federal) component and the federal (non-cost matching) component.

The amount of matching is subject to adjustment based on total allowable costs incurred. All costs and contributions used to satisfy the matching requirement must be documented by the recipient, including how the value for in-kind contributions was determined, and are subject to audit. The cost matching requirement is not negotiable for for-profit organizations.

All instructions in the SF424 (R&R) Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Specify whether the application is proposed for entry at the Discovery or Development stage.

Clearly indicate within a table which activities will be conducted by PD/PI and associated personnel (i.e. funded by the UG3/UH3 award) and which activities will be conducted by NIH contract research organizations and/or consultants. Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel.

Activities that will be conducted by NIH contractors need not be described in detail in the application since these will be planned after the award by the LDT. An overview of the goals, rather than a detailed plan, should be provided in